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Safety, efficacy, and immunogenicity of an inactivated influenza vaccine in healthy adults: a randomized, placebo-controlled trial over two influenza seasons
Lisa A Jackson1,
Manjusha J Gaglani2,
Harry L Keyserling3,
John Balser4,
Nancy Bouveret5,6,
Louis Fries7 &
John J Treanor8
BMC Infectious Diseases volume 10, Article number: 71 (2010) Cite this article
Seasonal influenza imposes a substantial personal morbidity and societal cost burden. Vaccination is the major strategy for influenza prevention; however, because antigenically drifted influenza A and B viruses circulate annually, influenza vaccines must be updated to provide protection against the predicted prevalent strains for the next influenza season. The aim of this study was to assess the efficacy, safety, reactogenicity, and immunogenicity of a trivalent inactivated split virion influenza vaccine (TIV) in healthy adults over two influenza seasons in the US.
The primary endpoint of this double-blind, randomized study was the average efficacy of TIV versus placebo for the prevention of vaccine-matched, culture-confirmed influenza (VMCCI) across the 2005-2006 and 2006-2007 influenza seasons. Secondary endpoints included the prevention of laboratory-confirmed (defined by culture and/or serology) influenza, as well as safety, reactogenicity, immunogenicity, and consistency between three consecutive vaccine lots. Participants were assessed actively during both influenza seasons, and nasopharyngeal swabs were collected for viral culture from individuals with influenza-like illness. Blood specimens were obtained for serology one month after vaccination and at the end of each influenza season's surveillance period.
Although the point estimate for efficacy in the prevention of all laboratory-confirmed influenza was 63.2% (97.5% confidence interval [CI] lower bound of 48.2%), the point estimate for the primary endpoint, efficacy of TIV against VMCCI across both influenza seasons, was 46.3% with a 97.5% CI lower bound of 9.8%. This did not satisfy the pre-specified success criterion of a one-sided 97.5% CI lower bound of >35% for vaccine efficacy. The VMCCI attack rates were very low overall at 0.6% and 1.2% in the TIV and placebo groups, respectively. Apart from a mismatch for influenza B virus lineage in 2005-2006, there was a good match between TIV and the circulating strains. TIV was highly immunogenic, and immune responses were consistent between three different TIV lots. The most common reactogenicity events and spontaneous adverse events were associated with the injection site, and were mild in severity.
Despite a good immune response, and an average efficacy over two influenza seasons against laboratory-confirmed influenza of 63.2%, the pre-specified target (lower one-sided 97.5% confidence bound for efficacy > 35%) for the primary efficacy endpoint, the prevention of VMCCI, was not met. However, the results should be interpreted with caution in view of the very low attack rates we observed at the study sites in the 2005-2006 and 2006-2007, which corresponded to relatively mild influenza seasons in the US. Overall, the results showed that TIV has an acceptable safety profile and offered clinical benefit that exceeded risk.
Trial registration
Annual epidemics of influenza due to influenza A and B viruses remain a substantial cause of morbidity and mortality worldwide, particularly among vulnerable groups such as people aged ≥ 65 years, children aged <2 years, and people with chronic medical conditions [1–3]. In addition to these identified risk groups, influenza is responsible for a substantial burden of illness, absenteeism, and resultant societal costs among otherwise healthy working adults [4–7]. Trivalent inactivated influenza vaccines (TIV) containing antigens of two influenza A strains (one A/H1N1 and one A/H3N2), in combination with antigens of one influenza B strain, provide the current standard for influenza prevention. Because one or more new antigenically drifted variants circulate annually, the vaccines must be updated to provide optimal protection against the predicted prevalent strains for the next influenza season [8–10]. The World Health Organization (WHO), as well as the US Food and Drug Administration (FDA) Center for Biologics Evaluation and Research, provide annual guidance for strain selection based on new drift variants detected through a global influenza surveillance network [8, 9].
Clinical trial data have repeatedly shown that TIVs can be protective against seasonal influenza, including seasons when the surface antigens of the prevalent virus(es) match the vaccine strains, and some seasons when a drifted strain circulates, although efficacy can be reduced as a result of substantial antigenic drift [8, 11–14]. However, many TIV studies have been either too small to provide narrow confidence limits about the point estimates for efficacy, or have used serological criteria to define the influenza infection endpoint, which unlike virus detection by culture or molecular methods, may bias the results in favor of the vaccine because detection of infection by seroconversion may be adversely affected by prior elevation of baseline titers in vaccinated, but not unvaccinated subjects [15, 16]. Furthermore, marked variations in efficacy estimates have been observed from season to season, even when the same investigators have applied identical methods to evaluate the same type of vaccine formulation in consecutive years [12, 13].
In this paper, we describe an efficacy, safety, and immunogenicity study of a trivalent inactivated split virus influenza vaccine (TIV; marketed, depending on the countries, as Fluviral ®, FluLaval™, or Griplaval™ trademarks of the GlaxoSmithKline group of companies). The product, first licensed in Canada in 1992, has undergone several process refinements, including introduction of a concentration step, homogenization, and sterile filtration. Following clinical studies of safety and immunogenicity in adults conducted in Canada and the US in the 2004-2005 influenza season, the product received accelerated approval from the FDA in 2006 [17]. The randomized, placebo-controlled study reported in this paper is part of the post-approval clinical trial program, conducted to confirm manufacturing consistency, and to further assess the clinical benefits of this TIV formulation using culture-confirmed efficacy endpoints[17].
The study included healthy adults aged 18 to 49 years in the US, and in order that a placebo control could be ethically employed, high-risk patients for whom annual influenza vaccine is recommended by the Advisory Committee on Immunization Practices (ACIP) were not eligible for inclusion [18]. The primary clinical endpoint was based upon rates of culture-confirmed influenza illness caused by A and/or B virus strains antigenically matching those in the vaccine. The study was conducted over the 2005-2006 and 2006-2007 influenza seasons.
Design and participants
This was a randomized, double-blind, placebo-controlled study of the efficacy of TIV in prevention of vaccine-matched, culture-confirmed influenza (VMCCI) conducted in the 2005-2006 and 2006-2007 influenza seasons in the US.
The original primary outcome measure defined by the study protocol was the average vaccine efficacy over two consecutive seasons in the prevention of culture-confirmed influenza. In correspondence following the 2005-2006 season, the FDA Center for Biologics Evaluation and Research noted that the season was marked by a significant frequency of circulation of influenza virus strains that were antigenically-drifted from those in the vaccine, and required that the protocol be modified to assess the average efficacy against VMCCI across both seasons as the primary measure of vaccine efficacy.
Male and female volunteers aged 18 to 49 years inclusive were eligible to participate if they were clinically healthy, understood the study procedures, had access to telephone contact throughout study, and provided informed written consent. In Season 1, eligible participants were enrolled at 37 centers, and in Season 2, eligible participants were enrolled at 44 centers.
Exclusion criteria included: a significant acute or chronic, or medical or psychiatric illness requiring institution of new medical or surgical treatment, or a significant dose alteration for uncontrolled symptoms or drug toxicity within 3 months; diagnosis of cancer, or treatment for cancer, within 3 years; systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg; a health condition placing the potential subject in a risk group recommended for routine influenza immunization by Advisory Committee on Immunization Practices (ACIP), e.g. chronic pulmonary (including asthma), cardiovascular, renal, hepatic, hematological, or metabolic disorders (including diabetes mellitus); immunosuppressive illness, recent/ongoing receipt of immunosuppressive therapy, or human immunodeficiency virus infection [18]; recent administration of other vaccine or immunoglobulin, contraindication to influenza vaccine, or previous influenza vaccination within 9 months. A negative pregnancy urine test at screening was required for women of childbearing potential before inclusion into the study, and women were required to use reliable contraception throughout the study. Individuals employed in professions prone to influenza transmission to or from high-risk populations, and individuals living in the same household as an immunocompromised person were not eligible to participate (also based on ACIP recommendations [18]).
In order to allow an independent assessment of efficacy in each season, participants who were enrolled in the study during 2005-2006 (Season 1) were not eligible for enrollment during 2006-2007 (Season 2).
The study was conducted in accordance with Good Clinical Practice, US regulatory requirements, and the Declaration of Helsinki. This protocol and consent for this multi-centered study were approved by six (6) independent ethics committees/institutional review boards as required to provide ethical oversight for 44 sites. The names of these bodies are on file with the corresponding author.
Vaccine allocation and administration
Treatment allocation was determined by blocked, stratified randomization with a 1:1 distribution to TIV or placebo; randomization was stratified by study center, age (18-34 and 35-49 years), and the subject's report of previous recent receipt (within ≤ 2 years) of TIV. Each study center had a pre-determined sequence of randomization numbers which were allocated sequentially to eligible subjects. Participants were allocated equally among 3 different vaccine lots. Clinic staff (excluding the nurse giving the vaccine), were blinded to the treatment group until the study was complete.
Participants received a single injection of TIV (FluLaval™, a trademark of the GlaxoSmithKline group of companies; manufactured by ID Biomedical Corporation of Quebec [IBD-Q], Canada), or saline placebo injection. Each 0.5 mL dose of TIV contained 15 μg of hemagglutinin (HA) antigen of each recommended influenza strain. Antigens for Season 1 (2005-2006) were A/New Caledonia/20/1999 (H1N1), A/New York/55/2004 (H3N2, A/California/7/2004-like), and B/Jiangsu/10/2003 (B/Shanghai/361/2002-like). Antigens for Season 2 (2006-2007) were A/New Caledonia/20/1999 (H1N1) virus, A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004. Three consecutive vaccine lots were used in each season.
The primary endpoint was the average efficacy over Seasons 1 and 2 for the prevention of culture-confirmed influenza illness due to influenza A or B virus strains antigenically matching those in the vaccine (i.e. vaccine-matched, culture-confirmed influenza; VMCCI). The case definition of VMCCI required the presence of influenza-like illness (ILI), defined as symptoms that interfered with normal daily activities and that included cough, and at least 1 additional symptom from among fever (oral temperature >37.7°C/99.9°F), headache, myalgia and/or arthralgia, chills, rhinorrhea/nasal congestion, and sore throat. Participants meeting the definition for ILI and with concurrent isolation from a nasopharyngeal swab of an influenza A and/or B virus isolate antigenically matching a vaccine strain for the relevant year were considered to be cases of VMCCI.
Co-primary safety endpoints were the assessment of solicited local and general reactogenicity events occurring between 0 and 3 days of vaccination, and unsolicited spontaneous adverse events (AEs) for a minimum of 135 days post-vaccination.
The average efficacy over Seasons 1 and 2 against culture-confirmed influenza illness (CCI), or laboratory-confirmed influenza illness (LCI) were secondary endpoints. CCI was defined as ILI with any influenza A or B virus isolate by culture, and LCI was defined as one or both of CCI or ILI with a 4-fold increase in hemagglutination-inhibiting (HI) serum antibody titers to a circulating influenza virus strain between Day 21 (± 4 days) post-vaccination and Final Visit specimens obtained after the end of the influenza season. The average efficacy across both seasons was also assessed according to age, prior vaccination status, and gender; but no attempt was made to provide statistical power for hypothesis tests within these subgroups.
Immunogenicity endpoints were HI assay-based Day 21 seroconversion and seroprotection rates, geometric mean fold-rises (GMFR) between Day 0 and Day 21, and lot equivalence according to reciprocal GMTs at Day 21 in Season 1.
The surveillance period in each season was ~15 weeks. Surveillance for influenza was conducted between 14 November 2005 through 30 April 2006 (Season 1), and 13 November 2006 through 30 April 2007 (Season 2). Throughout the influenza season, participants were instructed to report symptoms meeting the definition of ILI via a study-specific, toll-free telephone number within 48 hours of symptom onset, and to record temperatures and symptoms during ILI episodes. This passive surveillance method was accompanied by active surveillance in which ILI symptoms were solicited during weekly outbound telephone contact. Local visiting nurses were dispatched to participants fulfilling the definition of ILI within 24 hours of reporting, and obtained nasopharyngeal and oropharyngeal swabs for viral culture. To ensure that influenza illnesses were detected, participants could be swabbed more than once.
Antigenic characterization and serology
Blood samples were taken before vaccination on Day 0, and at the next study visit on Day 21 (± 4 days), and at the Final Visit, which was within 4 weeks following the end of the surveillance period. Following serum separation, samples were frozen until analysis. Combined nasopharyngeal and oropharyngeal swab samples from participants reporting ILI were refrigerated and transported to a central laboratory (Covance Central Laboratory Services, Inc., Indianapolis, US) for influenza virus culture and assessment of CCI. Samples were cultured using primary monkey kidney cells, and influenza A and B viruses were identified using immunofluorescent staining with influenza-specific monoclonal antibodies. Influenza A viruses were further sub-typed by immunofluorescence using H1 and H3 specific reagents.
Detailed antigenic characterization and vaccine match analysis (i.e. VMCCI) of the influenza viral isolates was determined by serologic methods in the laboratory of Dr John Treanor (University of Rochester Medical Center [URMC], New York, US), using ferret sera for influenza A virus strains (kindly provided by Dr Alexander Klimov, CDC, Atlanta, Georgia, US), or WHO typing sera for B lineages. Isolates were considered to be 'vaccine matching' if there was a ≤ 4-fold difference in the HI titer of the subject isolate strain and the vaccine prototype strain with reference anti-serum [19]. Testing included TIV virus strains, and drifted influenza A virus strains or alternate-lineage influenza B virus strains circulating in each year. The isolate type and subtype were also confirmed using reverse transcription polymerase chain reaction (RT-PCR; GSK Biologicals, Rixensart, Belgium). RT-PCR confirmed the isolate type and subtype determined by immunofluorescence and/or HI testing for 100% of isolates.
To evaluate the endpoint of LCI, Day 21 and Final Visit sera of all participants who reported ILI, irrespective of culture-confirmation, were tested for seroconversion. Immunogenicity of the vaccine was examined by testing of Day 0 and Day 21 serum samples in a randomly selected subset of participants. Immunogenicity was assessed using established HI assay methods performed at the IBD-Q analytic laboratory (IBD-Q/GlaxoSmithKline Biologicals North America Clinical Immunology Laboratory, Laval, Quebec, Canada) [20].
Reactogenicity and safety
After the injection, participants were observed for 30 minutes for local and/or systemic reactogenicity, and oral temperature was taken. Participants received memory aids to record the severity of injection site reactions, reactogenicity events, and general solicited adverse events (AEs). Definitions of events and severity grades were provided with the memory aids. Participants reported immediate reactogenicity data (within 30 minutes of dosing) before leaving the clinic, and solicited reactogenicity symptoms (occurring on Day 0 from 30 minutes post-vaccination to the evening of Day 3) no later than 8 days post-vaccination via an Interactive Voice Response System (IVRS).
Data on AEs and serious adverse events (SAEs) were reported throughout the entire study period. AEs were captured using electronic case report forms and coded by preferred term and primary system organ class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA).
Sample size calculations were based on the Farrington-Manning method, as implemented in the PASS software package. We assumed a vaccine efficacy of 70% and a rate of culture-confirmed influenza (CCI) of 2.0% in placebo recipients in each season. The originally planned sample size was selected to provide 80% power in a one-sided test with type 1 error = 0.025 to reject the null hypothesis that the average vaccine efficacy was less than 35%. An adjustment of 10% was applied to account for potential drop-outs, resulting in a target of 3187 participants per study arm across both seasons (total 6374). After the end of Season 1, at the request of the regulatory authority (US FDA, Center for Biologics Evaluation and Research), the primary study endpoint was changed from CCI to vaccine-matching, culture-confirmed influenza illness (VMCCI).
As specified in the protocol, at the end of Season 1 an unblinded, independent statistician, who was not otherwise involved in the analysis, evaluated the actual rate of CCI detected during Season 1. This had originally been planned to ensure that the estimated sample size across both seasons would confer sufficient power to demonstrate average efficacy against CCI with the requisite degree of precision and to allow adjustment of the sample size in Season 2 if needed. Given the change in the primary endpoint, this determination also involved estimation of the proportion of influenza isolates identified from the placebo group that would be antigenically matched to the vaccine strains, to ensure that the study would be adequately powered for the endpoint of VMCCI. Therefore, the statistician assumed that 66.8% of influenza isolates identified in the placebo group in Season 1 (all of which had not yet been sub-typed) were antigenically matched to the vaccine strains, based on 2005-2006 US surveillance data, and that 80% of influenza isolates identified from the placebo group in Season 2 would be antigenically matched to the vaccine strains, based on the mean and median values of US surveillance results for the preceding 6 years [21]. Based on these estimations and the actual CCI attack rate identified in Season 1, the enrollment target for Season 2 was increased from 3187 to 3900 participants.
The primary analysis was performed on the Per-Protocol (PP) set including participants who received the treatment to which they were randomized, responded to ≥ 1 post-vaccination active surveillance telephone call, and with no major protocol deviations considered to affect the efficacy or immunogenicity data. Exclusions from the PP set were determined and documented before unblinding. The possible introduction of biases by use of the PP set was assessed by repeating efficacy analyses in the ITI set, which was the PP set plus participants with protocol deviations and treatment errors, and analyzed as randomized. Immunogenicity was evaluated in a randomly selected subset of participants (immunogenicity set).
The primary efficacy analysis was based on the average efficacy over Seasons 1 and 2 and assessed the null hypothesis that the average efficacy in the actively immunized group was ≤ 35%, against the alternative hypothesis that average efficacy was >35%. Average efficacy was defined as 1 - v(R1R2) × 100 where R1 and R2 were the relative risks of a given disease endpoint in Seasons 1 and 2, respectively. A one-sided 97.5% CI was constructed for the average efficacy, and the TIV efficacy target was to be established if the lower bound of the CI was >35%.
The seroconversion rate was defined as the proportion of participants with a ≥ 4-fold increase in reciprocal HI titer at Day 21 versus Day 0, or a reciprocal HI titer of ≥ 40 from a starting value <10; seroprotection rate was the proportion of participants with HI titers ≥ 1:40 at Day 21. The geometric means of reciprocal HI titers (GMTs) were calculated for Day 0 and Day 21 samples, and the geometric mean fold-rises (GMFR; geometric mean of the within-subject fold increases from Day 0 to 21) were also calculated. Lot equivalence was assessed using reciprocal GMTs at Day 21 in the immunogenicity set in Season 1. The Zmin method of Wiens and Iglewicz (WI) was used to assess overall lot equivalence with a two-sided 0.05 significance level and power of ≥90% [22]. One-sided 97.5% lower confidence bounds (identical to two-sided 95% lower confidence bounds) on the rate of seroconversion, seroprotection, and GMT were calculated with each Season.
The safety set included participants who received any study treatment and had any post-vaccination safety data. If an incorrect treatment was conclusively documented, participants in the safety set were analyzed based on the treatment they actually received. The incidence of immediate complaints, reactogenicity events from Day 0 to Day 3, and unsolicited AEs were compared between the TIV and placebo groups using Fisher's exact tests. Any reactogenicity event at grade 2 or 3 with an incidence of >10% was assessed using an extended Mantel-Haenszel test. Statistical analyses of safety were performed at the two-sided significance level of 0.05, with no correction for multiple comparisons.
Participant enrollment in Season 1 began 17 September 2005 and follow-up ended 31 May 2006, and enrollment in Season 2 began 16 October 2006 and follow-up ended 6 June 2007. A total of 7611 participants received treatment; 3783 participants received TIV, and 3828 received placebo. A total of 7219 (95%) of vaccinated participants completed the study (Figure 1). The PP set included 3714 participants in the TIV group, and 3768 participants in the placebo group. No participants with culture-confirmed influenza illness were excluded from the primary analysis.
Enrollment and Inclusion in Analysis Sets over Two Seasons.
There were no significant differences between the treatment groups for any baseline characteristic (Table 1). In both groups, 57% of participants were aged 18-34 years, and 43% were aged 35-49 years.
Table 1 Demographic and clinical characteristics of study participants.
Vaccine efficacy
The average attack rate for VMCCI over Seasons 1 and 2 was low at 23/3714 (0.6%) in the TIV group, and 45/3768 (1.2%) in the placebo group (Table 2). The VMCCI attack rate in the placebo group in Season 1 (1.7%) was lower than, but similar to, the assumption used for the original sample size estimate (2.0%). In Season 2, the attack rate for VMCCI in the placebo group was extremely low at 0.7% and was much lower than the assumed attack rate of VMCCI of 1.6% that had been used to determine the revised sample size for enrollment in Season 2.
Table 2 Vaccine efficacy against VMCCI, CCI, and LCI in the Per-Protocol analyses.
The average efficacy of TIV for the prevention of VMCCI was 46.3%, with a one-sided 97.5% CI lower bound of 9.8%, thus the null hypothesis of efficacy ≤ 35% could not be rejected. Attack rates for CCI and LCI over Seasons 1 and 2 were higher than the attack rates of VMCCI, but were still relatively low. In the TIV and placebo groups, attack rates for CCI were 0.8% and 1.6%, respectively, and the average efficacy of TIV against CCI was 49.3% with a 97.5% CI lower bound of 20.3%. The attack rates for LCI in the TIV and placebo groups were 1.2% and 3.2%, respectively, and the average efficacy of TIV against LCI was 63.2% with a 97.5% CI lower bound of 48.2% (Table 2). The results of the efficacy analyses conducted using the ITI set were essentially identical to those using the PP set; differing by only 0.1% for each of the VMCCI, CCI, and LCI endpoints (data not shown).
The antigenic characteristics of the influenza A and B viruses isolated from study participants showed good general concordance with CDC surveillance data in the same years [23, 24]. In both Seasons 1 and 2, there was limited antigenic drift among A/H3N2 strains, and efficacy against disease associated with H3N2 isolates differed minimally for vaccine-matched strains (VMCCI) and all strains (CCI), or between seasons. No A/H1N1 viruses were isolated in Season 1, and in Season 2, overall efficacy against A/H1N1 was low at 23.9%, although this was based on a very small number of cases (6 in the TIV group, 8 in the placebo group). In Season 1, in which a Yamagata-lineage B virus was used in the vaccine and all B virus isolates were found to be of the Victoria lineage, there was thus by definition no VMCCI, and observed efficacy against CCI for Victoria lineage viruses was 0. In Season 2, in which B/Malaysia/2506/04 (a Victoria-lineage virus) was used in the vaccine, the point estimate for efficacy against VMCCI due to influenza B viruses was 100%, while the point estimate for efficacy against disease associated with Yamagata-lineage B viruses was 66% (estimates again based on small case numbers, with broad 95% confidence bounds).
The average efficacy of TIV against VMCCI was slightly higher in the 18-34 years stratum at 51.6% (97.5% CI lower bound 44.5%), than in the 35-49 years stratum at 44.5% (97.5% CI lower bound -11.8%), but this difference was not statistically significant (p = 0.79). Unexpectedly, the average efficacy against VMCCI was much lower in women, 19.4% (97.5% CI lower bound -42.8%), than in men, 89.0% (97.5% CI lower bound 53.0%; p value for the male:female contrast 0.0123). A similar, although slightly less marked trend between sexes was observed for the average efficacy of CCI and LCI (data not shown). Overall, women in this trial were marginally older than men (mean ± SD: women 33.3 ± 9.14 years; men 31.7 ± 9.12 years) and had a slightly higher rate than men of recent (within ≤ 2 years) previous influenza vaccine (women, 21%; men, 16%; p < 0.0001); these differences were similar in the TIV and placebo groups.
In the PP set, ILI symptoms were reported by a total of 362/3714 (10%) participants in the TIV group, and 427/3768 (11%) participants in the placebo group. An ad hoc analysis was conducted to assess efficacy when the definition of ILI was restricted to include fever (defined by self-observed oral temperature ≥ 38°C). With this modification, the average efficacy of TIV against VMCCI was 58.0%, with a 97.5% CI lower bound of -21.5% (due to fewer cases), and the average efficacy of TIV against CCI was 66.8%, with a 97.5% CI lower bound of 7.2%.
The PP immunogenicity set included 1514 randomly selected participants, of which 1298 received TIV and 216 received placebo. TIV was highly immunogenic in Seasons 1 and 2 (Table 3). Immune responses were similar in both seasons for the A/H1N1 and the B virus components. HI GMTs increased 9.94-10.96-fold after immunization for the A/H1N1 component (A/NewCaledonia/20/99 in both seasons), with 68% seroconversion rates in each season. GMTs increased 11.45-12.36-fold for the B virus components, with 82% seroconversion to B/Jiangsu/10/03 (a Yamagata lineage virus) in Season 1 and 74% seroconversion to B/Malaysia/2506/04 (a Victoria lineage virus) in Season 2. Responses differed between seasons for the A/H3N2 component, with a stronger response in Season 1 to the A/New York/55/2004 antigen (15.84 fold-rise in GMT and 85% seroconversion rate) than in Season 2 to the A/Wisconsin/67/2005 antigen (10.59 fold-rise in GMT and 72% seroconversion rate). Despite this difference, the two-sided 95% CI lower bound for the proportions of active vaccine recipients attaining post-immunization HI titers ≥ 1:40 were ≥ 90% for all vaccine strains in both seasons.
Table 3 Summary of immunogenicity data in the immunogenicity set.
Treatment with placebo had a negligible effect on HI titers in both seasons. In view of the unexplained gender difference in efficacy noted above, a post-hoc examination of immune response by gender was performed. The seroconversion rate for the A/New Caledonia H1N1 antigen was lower among women than men in both seasons, and lower GMTs for this virus were found among women (318.6) compared with men (414.6) in Season 2; however, the proportion of men and women with A/New Caledonia/20/99 HI titers ≥ 1:40 was ≥ 96% in both seasons, and there were no other immunogenicity differences of note between men and women (Table 4).
Table 4 Summary of immunogenicity in men and women receiving TIV in the immunogenicity set.
In Season 1, immunogenic lot consistency based on GMT values was demonstrated using the Zmin statistic by the method of Wiens and Iglewciz [22], and according to the study protocol, was not retested in Season 2 (data not shown).
One or more solicited events after immunization occurred in 2487/3783 (66%) participants in the TIV group and 1675/3828 (44%) participants in the placebo group (p < 0.0001) (Table 5). Common reactogenicity complaints (30 minutes post-vaccination through Day 3) that were significantly more frequent in the TIV versus the placebo group included pain/soreness at the injection site (51% and 14%, respectively), tiredness (20% and 18%, respectively), and myalgia and/or arthralgia (18% and 10%, respectively). Less frequent, but also significantly associated with active treatment, were malaise and redness and/or swelling at the injection site. Oral temperatures of ≥ 37.5°C/99.9°F were reported by 3% of TIV recipients and by 1% of placebo recipients (p = 0.0005); however, the great majority of these reports included maximal temperatures of ≤ 38.5°C/101.3°F. From Day 0 through Day 3 post-vaccination, there was no significant association between TIV vaccination and reports of headache, red eyes, cough, sore throat, and hoarseness or pain on swallowing.
Table 5 Incidence of TIV reactogenicity events from Day 0† to Day 3 in the Safety Set
In both groups, the most frequent unsolicited AEs from Days 0 through Day 21 with TIV and placebo were pharyngolaryngeal pain (120/3783 and 120/3828, respectively [both 3%]), headache (118/3783 and 121/3828, respectively [both 3%]), and fatigue (108/3783 and 120/3828 [both 3%]). Overall, the rate of AE reports in the TIV group was 808/3783 (21%) and in the placebo group was 736/3828 (19%) (p = 0.021).
From Day 0 to Final Visit, the incidence of unsolicited AEs by SOC reported by ≥ 1% of participants was higher with TIV than placebo, with injection site pain (95/3785 [3%] and 30/3828 [1%], respectively; p < 0.0001), and injection site erythema (45/3783 [1%] and 9/3828 [<1%], respectively; p < 0.0001) accounting for the between-group difference. No other significant differences were seen between groups for incidence rates of AEs by SOC.
Unsolicited SAEs were uncommon, and were reported by 1% of participants in both treatment groups. Overall, 44/3783 (1%) and 39/3728 (1%) of participants in the TIV and placebo groups, respectively, experienced at least 1 SAE. All SAE types occurred in ≤ 1% of participants. None of the SAEs were considered by the investigators to be vaccine-related. One subject in the placebo group had a fatal road traffic accident during the study. Severity of ILI was not systematically assessed; a single subject in the placebo group was hospitalized with a diagnosis of influenza.
Pregnancies
There were a total of 25 pregnancies in the TIV group, and 32 in the placebo group, of which 4 (16%: 95% CI; 5%, 36%) and 7 (22%: 95% CI; 9%, 40%), respectively, ended in spontaneous abortion. Three pregnancies were electively terminated. One placebo recipient was induced at 34 weeks because of intrauterine growth retardation, and the infant was reported to have 2 hernias, which were surgically repaired, and a heart murmur. Two pregnant participants were lost to follow up, and there were 18 (72%) and 22 (69%) full-term births with healthy infants in the TIV and placebo groups, respectively.
Although inactivated influenza vaccines are recommended for many populations, estimates as to their true efficacy vary widely. It is commonly held that the efficacy of TIVs is 60 to 80% in healthy younger adults and similar in children over the age of 2 years, but less in the elderly (particularly the chronically-ill or institutionalized) [25–29]. The degree of antigenic match between the vaccine and circulating virus strains, the exact illness endpoint used, and the surveillance methodology in clinical trials can influence efficacy estimates. Efficacy data concerning children under 2 years of age are very limited.
This placebo-controlled, randomized study was conducted to assess the efficacy, safety, and immunogenicity of a TIV over the 2005 2006 (Season 1) and 2006 2007 (Season 2) influenza seasons in healthy adults in the US. The primary endpoint was protection against VMCCI, as requested by US regulatory authorities, rather than the frequently cited endpoints of CCI or LCI. Although the LCI endpoint has been questioned by some authors [15], it is still widely used, and constitutes the primary endpoint for the majority of the published TIV efficacy experience.
Despite a good degree of 'vaccine-match' among the influenza isolates in the trial (75.5%), and a strong immune response to the vaccine in both years, the average efficacy over Seasons 1 and 2 of TIV against VMCCI was only 46.3%, with a one-sided 97.5% CI lower bound of 9.8%. While the vaccine was clearly efficacious relative to placebo (one-sided 97.5% CI lower bound for efficacy excluded 0), these results did not satisfy the pre-defined criterion for success, i.e. exclusion of efficacy of ≤ 35% (as evidenced by a lower 97.5% CI of >35%). The results were similar for CCI, with an average efficacy of 49.4%, with one-sided 97.5% CI lower bound of 20.3%, the CI becoming narrower due to the greater number of cases.
Efficacy was higher for the LCI endpoint, at 63.2%, with one-sided 97.5% CI lower bound of 48.2%; this is generally consistent with previously reported TIV efficacy estimates in studies using this endpoint [12, 14, 30]. While an intrinsic bias of the LCI endpoint in favor of the vaccine has been noted [15, 16] and, therefore, limits its utility for regulatory purposes, it should also be noted that this endpoint may improve sensitivity relative to culture. In addition, the endpoint of LCI has been used in many prior clinical trials of TIV, yielding estimates of TIV efficacy in adults of about 70% [14, 15]. Thus, the estimated vaccine efficacy against LCI in this trial is consistent with that estimated in prior trials of other TIVs.
A key factor influencing efficacy findings in influenza vaccine studies is the disease attack rate, and the unpredictable nature of epidemic intensity poses a challenge when planning influenza vaccine efficacy trials [12, 13, 25, 31]. Our study was powered on the assumptions that vaccine efficacy would approximate 70%, based on the prior literature reporting culture-confirmed influenza endpoints, and that the attack rate for CCI in the placebo group would be 2.0% across both seasons. The attack rate assumption was adjusted in Season 2 to 1.6% based on the regulatory request to adopt VMCCI as the primary endpoint, and the sample size correspondingly increased. The actual VMCCI attack rate in placebo recipients in Season 1 was close to our prediction, but in Season 2 the attack rate was less than half of that predicted, and this had a large negative impact on the precision of the average efficacy estimate. Despite this, it was also clear that the efficacy observed did not differ markedly between the seasons, and might not have sufficed to exclude the 35% lower bound of the primary hypothesis even if the VMCCI attack rates in Season 2 had matched those in Season 1.
Similar to the findings of our study, the Centers for Disease Control and Prevention surveillance data summaries for the 2005-2006 and 2006-2007 influenza seasons in the US suggest that these were relatively mild influenza seasons [23, 24]. The weekly percentage of outpatient visits to US sentinel providers for ILI peaked twice in the 2005-2006 season at 3.3% and 3.2% (baseline 2.2%), and peaked twice in the 2006-2007 season at 3.0% and 3.5% (baseline 2.1%) [23, 24]. In the prior three seasons, the peak percentage of outpatient visits for ILI had ranged from 2.3% to 7.6% [23, 24].
A negative impact of low attack rates in a given season on point estimates of efficacy has been well documented. Previous studies of a TIV product, involving the same investigators, methods, and source populations over successive seasons, have reported dramatic differences in efficacy estimates between seasons, without obvious explanation based on circulating strain match to the vaccine [12, 13]. In these studies, the low efficacy estimates were found in seasons with lower overall attack rates [12, 13]; a similar experience has occurred in pediatric trials [31]. While a clear reason for this phenomenon is not apparent, it can be speculated that low background attack rates may result from either relatively high pre-existing population resistance to the circulating strain(s), or modest intrinsic virulence of the circulating strains, such that only intense exposures lead to disease. In either case, the attainable impact of a vaccine might be blunted. Primary detection of influenza virus infections in this study was by means of viral culture; with the use of molecular methods confined to characterization of isolates. Other reports have suggested that the use of RT-PCR as a primary detection tool may improve the rate of ascertainment of influenza virus infections by 20 to 30% [12, 13, 31, 32], but this maneuver does not appear, in and of itself, to have a major impact on point estimates of efficacy.
As suggested previously, a further factor that may compromise vaccine efficacy is the extent of antigenic drift and the degree of match between vaccine and circulating viruses [11, 12, 33]. In our study, the majority of cases in both seasons were due to influenza A/H3N2 viruses, and antigenic drift was modest and had little apparent impact. However, only 5/17 cases of culture-confirmed influenza B disease were due to viruses of the same lineage as the vaccine strain in the relevant season (data not shown), and average efficacy against non-matching B strains was low (~16%); this result clearly reduced the estimate of efficacy against all CCI.
The definition of influenza-like illness (ILI) in our study required that illness impeded normal daily activities, with cough plus ≥ 1 other symptom from a panel including both respiratory and systemic complaints, so this allowed for a diagnosis without need for a systemic symptom (i.e. fever, myalgia/arthralgia). Cough has been previously found to be one of the most sensitive clinical indicators of influenza, but has little specificity, whereas fever is a classically-cited characteristic of influenza, with substantial positive predictive value, but lower sensitivity [34]. Fever was not made a requirement for ILI in our study in order to maximize sensitivity. However, our ad hoc analyses showed that narrowing of the case definition to require fever reduced the case rate but notably improved the apparent efficacy of TIV. A potential interpretation of this finding may be that TIV is most effective against severe manifestations of influenza, and less so against illnesses with predominantly respiratory symptoms. Although efficacy against severe disease is desirable, the relatively sensitive but non-specific case definition in our study may have allowed for the inclusion of respiratory illness caused by mixed infections in which influenza viruses may have been minor or coincidental. An additional factor that could have compromised the results is the highly decentralized source of the specimens, and the transportation of specimens to a centralized laboratory may not have been optimal for the recovery of influenza viruses from nasopharyngeal swabs.
An unexpected finding of the study was the difference between men and women for the primary endpoint: men, 89.0%; and women, 19.4%. Women were slightly older than men (33.3 and 31.7 years, respectively), and were more likely to have had previous recent influenza vaccination (21% and 16%, respectively). These between-gender differences were reflected in both treatment groups, which were well matched for all baseline characteristics. In addition, all three viruses were culture-confirmed in men and women, there was no differential temporal clustering of cases, and serum HI titers did not differ meaningfully between the sexes (data not shown); this is in contrast to a previous large study of a TIV, which reported significantly higher GMT responses in women than men, regardless of age or dose or influenza strain [35]. The attack rate of VMCCI among placebo-treated men and women was similar (1.27% and 1.14%, respectively), which suggests that both sexes had a similar level of exposure. At present, the difference in values between men and women remains unexplained and must be viewed with caution because a further subdivision of the already-small case numbers results in very broad CIs about the efficacy estimates.
In terms of seroconversion and rates of attainment of post-vaccinal HI reciprocal titers ≥ 40 ("seroprotection" rates), the TIV in this study fulfilled the immunogenicity criteria for the accelerated approval of seasonal influenza vaccines established by the US FDA Center for Biologics Evaluation and Research for all strains in both seasons [36]. In addition, manufacturing consistency was confirmed for three consecutive TIV lots in the 2005-2006 season, based on GMT values. Vaccine immunogenicity as measured by induction of hemagglutination-inhibiting antibodies provides a marker of potential vaccine effectiveness in the absence of viral circulation and has therefore been, and continues to be, a useful tool for the registration of influenza vaccines. Nevertheless, definitive demonstration of a single antibody titer which constitutes an absolute correlate of protection for all virus strains remains elusive, and the current study was not designed to demonstrate this.
The reactogenicity events reported in the study were consistent with those commonly reported with TIVs. Reactogenicity events that were significant in the TIV versus placebo group included injection site pain, injection site redness and swelling, myalgias, arthralgias, fever and fatigue; the majority of events were mild (grade 1) in severity. There was a slightly higher incidence of spontaneous AEs in the TIV versus placebo group reported up to 21 days post-vaccination, and this was primarily due to the persistence of injection site pain and redness. Overall, the results suggest that the safety profile of TIV was acceptable, and consistent with the historical performance of similar products.
This randomized, placebo-controlled trial showed that the average efficacy of TIV for the prevention of VMCCI over the 2005-2006 and 2006-2007 influenza seasons was 46.3%. Although the differences between the vaccine and placebo groups in the primary endpoint did not meet the pre-defined criterion for success, the TIV clearly demonstrated clinical benefit (i.e. it was readily differentiated from placebo by all culture and/or laboratory-confirmed influenza endpoints) and the primary endpoint result must be interpreted with some caution in view of the very low influenza attack rates in both seasons; a factor which has previously been associated with low efficacy estimates in influenza vaccine trials. Furthermore, the immune responses to TIV fulfilled the licensure criteria for seasonal influenza vaccines [36]. Overall, TIV had a safety profile that was considered to be acceptable, and was consistent with other inactivated influenza vaccines.
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Pre-publication history
The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/10/71/prepub
We are grateful to the National Institute for Biological Standards and Control (NIBSC, UK) for providing the vaccine virus strains. The authors are indebted to the participating clinicians, sub-investigators, nurses, research coordinators, and laboratory technicians at the study site and the sponsor's project staff for their support and contributions throughout the study. We also want to thank the study volunteers. We would like to thank the laboratory staff for their excellent, sedulous immunological laboratory work. Finally we would like to thank Annick Moon (independent, UK) for her assistance in preparing the manuscript and Isabelle Camby for coordination.
Group Health Research Institute, Seattle, Washington, USA
Lisa A Jackson
Section of Pediatric Infectious Diseases, Scott & White Memorial Hospital and Clinic, Texas A&M University Health Science Center College of Medicine, Temple, Texas, USA
Manjusha J Gaglani
Division of Pediatric Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA
Harry L Keyserling
Veristat, Inc, Holliston, Massachusetts, USA
John Balser
GlaxoSmithKline Biologicals, Laval, Quebec, Canada
Nancy Bouveret
Variation Biotechnologies Inc, Gatineau, Québec, Canada
GlaxoSmithKline Biologicals, Columbia, Maryland, USA
Louis Fries
Infectious Diseases Unit, University of Rochester Medical Center, Rochester, NY, USA
John J Treanor
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Correspondence to Lisa A Jackson.
GSK Biologicals was the funding source and was involved in all stages of the study conduct and analysis. GSK Biologicals also took in charge all costs associated with the development and the publishing of this manuscript. The corresponding author had full access to the data, and final responsibility for submission of the manuscript for publication.
LJ has received research funding from manufacturers of influenza vaccines, including GSK, Sanofi Pasteur, and Novartis and has served as a consultant to GSK and Novartis. Dr Harry Keyserling received grant support from GlaxoSmithKline to conduct the study. JB has no conflict of interest to declare. NB is a former employee of GlaxoSmithKline Biologicals and reports ownership of equity or stock options. LFF is a full-time employee of GlaxoSmithKline. JT discloses having received laboratory support from GSK and MerciaPharma, as well as clinical trial support from Protein Sciences Corporation, Vaxinnate, Ligocyte, Wyeth, Bavarian Nordic, Sanofi and PaxVax. JT discloses scientific advisory board activities for Immune Targeting Systems and Toyama Chemical Concern.
All authors participated in the design, implementation, analysis and interpretation of the study. All authors read and approved the final manuscript. LF and NB were involved in all phases of the study, and led the clinical team at GSK Biologicals. LAJ, MJG and HLK led the clinical team at their respective centers, JB conducted the data analysis. JJT managed the team responsible for detailed antigenic characterization and vaccine match analysis.
Jackson, L.A., Gaglani, M.J., Keyserling, H.L. et al. Safety, efficacy, and immunogenicity of an inactivated influenza vaccine in healthy adults: a randomized, placebo-controlled trial over two influenza seasons. BMC Infect Dis 10, 71 (2010) doi:10.1186/1471-2334-10-71
DOI: https://doi.org/10.1186/1471-2334-10-71
Vaccine Strain
Attack Rate


MONTREAL – The McGill University Redmen, who captured their first-ever Baggataway Cup as Canadian University Field Lacrosse Association champs last fall, have won a bid to host the 2013 CUFLA national championship, Nov. 1-3.
It will mark the first time that McGill has won a bid to host the six-team event, although the University previously hosted part of the 2005 tourney when a snowstorm in Lennoxville, Que., forcing one semifinal game to be moved to the McGill campus.
The 13-member league, which includes three Quebec-based teams and 10 from Ontario, voted 9-2 in favour of McGill's bid, with two abstentions.
The six-team format will feature five games within 48 hours – two quarter-finals on a Friday night (Nov. 1), two semifinals on Saturday afternoon (Nov. 2) and the Baggataway Cup final on Sunday (Nov. 3). The first two games are scheduled to be held on the artificial surface at Forbes Field, located beside the student residences, while the remaining contests are slated for Molson Stadium.


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Assignment On Unemployment In Australia
1624 words - 7 pages
Unemployment, particularly long term unemployment, is the most savage cause of poverty and disadvantage in our community. It is the cause of enormous personal and financial hardship for hundreds of thousands of people and their families. Unemployment is the greatest determiner of poverty and exclusion--and that is why the fight against unemployment is so critically important. However it is said that this battle can only result in victory by concentrating on providing jobs and opportunities rather than penalties or slogans.The importance of employment can only be explained, in that undertaking paid work fulfils many functions in our society. Employment is the main way of receiving money ...view middle of the document...
People face a number of barriers to employment. The primary barrier is that there are not enough jobs for those who wish to undertake paid employment. In February 2002 there were still seven job-seekers for every job vacancy. There are also not enough supports available for people seeking paid work, such as access to affordable child care and rehabilitation or support mechanisms for people with disabilities. Also, paradoxically, people are often considered too young or too old by prospective employers, so age can also be a barrier to employment. Other barriers relate to where people are living. There are differences between rural and urban levels of unemployment, and also stark differences between suburbs in all major Australian cities.The unemployment rate is a figure produced monthly by the Australian Bureau of Statistics (ABS). An unemployed person is defined by the ABS as someone not in paid employment who is actively looking for work. Anyone who is doing paid work for at least one hour a week is not considered to be unemployed. Many people are marginally attached to the labour force--they want to work but are not actively seeking employment. Sometimes people stop looking for work because they are under the misleading impression that they won't be successful. These discouraged job seekers may believe they are too old, or too young, or do not possess the skills an employer would want. This is hidden unemployment. The other large group of people not represented in the statistics are those who are working but would prefer to work more hours, the underemployed. In February 2002, over 27 per cent of part-time workers wanted to work more hours .Three sources of data are used to calculate the figures representing the labour force in regard to unemployment. These involve the monthly labour force survey conducted by the Australian Bureau of Statistics, statistics from the Job Network and statistics from Centrelink. Also, the Australian Bureau of Statistics take sit further in that they attempt to categorize the final statistics into sections involving age, region, sex, occupation and education.Currently, as previously mentioned, the Australian Bureau of Statistics states that the unemployment rate in Australia is approximately 6.3% and nevertheless, this figure does not encapsulate hidden employment. Unfortunately, anyone can become unemployed readily. Statistically, however, indigenous Australians, recently arrived migrants, people with disabilities, young people and older workers who have been retrenched are most likely to be unemployed. People living in remote and rural communities also have higher rates of unemployment. The graph above shows the percentages of people in different age groups who were unemployed and looking for work in March 2002. Youth unemployment is very high across Australia. There are, however, fewer young people looking for work than in the past, as more undertake education and training before entering into the ...
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2772 words - 12 pages Great Depression include buying stock on margin, overproduction of goods, and under consumption due to lagging wages. The Great Depression resulted in High Unemployment, High inflation, Home and farm foreclosures, and business failures. The Great Depression spread around the world. Some countries looked for strong leaders to solve their countries problems due to the depression. This led to the rise of totalitarian dictators like Hitler and
The Themes Of Dejection In The Writing Of Wordsworth And Coleridge
Paper On The Giant Panda Of China
Assignment On Managing Performance And Change
The Influence That Christianity Had On Public Morality And Education In Australia Throughout ...
Hotbed Of Volcanic Activity Found Beneath Arctic Ocean
Essay On "The Metamorphosis" By Franz Kafka
'Many People Contribute To The Tragedy'
Response To The Text, "Animal Farm"

redpajama_set_name: RedPajamaCommonCrawl


text:
Samuel Andreas "Sam" Knabl (* 16. Juli 1982) ist ein ehemaliger österreichischer Basketballspieler und stammt aus Wolfsberg. Der 2,06 m große und 104 kg schwere Forward ist vierfacher österreichischer Meister und zweifacher Sieger im Supercup. Er spielte außerdem 26 Mal im österreichischen Nationalteam.

Leben
Knabl kam in Wolfsberg mit dem Basketball in Berührung. Im Alter von 17 Jahren wechselte Knabl 1998 zu den Kapfenberg Bulls, mit denen er in den Jahren 2001 bis 2004 vier Meistertitel und zwei Titel im Supercup (2002 und 2003) gewinnen konnte. Danach spielte er bei den kelag Wörthersee Piraten und dem UBSC PBS Graz. Seit 2008 war Knabl wieder Spieler und Mannschaftskapitän der Kapfenberg Bulls.

2013 verabschiedete er sich vom Leistungsbasketball, er hatte 398 Bundesligaspiele und 33 Partien im Europapokal bestritten. Im Amateurbereich spielte er nach seiner Bundesligazeit noch für Gratkorn.

Stationen
 1998–2005  Kapfenberg Bulls
 2005–2006  kelag Wörthersee Piraten
 2006–2007  UBSC PBS Graz
 2008–2012  Kapfenberg Bulls

Literatur
 Ernst Weiss (Hrsg.): Basketball-Guide 2008/09. Eigenverlag, Wien 2008.

Einzelnachweise

Weblinks
 Porträt von Samuel Knabl auf der Homepage der Kapfenberg Bulls (abgerufen am 10. August 2009)

Basketballspieler (Kapfenberg Bulls)
Österreichischer Meister (Basketball)
Basketballspieler (Wörthersee Piraten)
Basketballspieler (UBSC Raiffeisen Graz)
Österreicher
Geboren 1982
Mann

redpajama_set_name: RedPajamaWikipedia


text:
What's It All About?
The artist signs copies of the recently-published book documenting Shoreline Project, the 2018 Art & Nature commissioned work.
Included with museum admission. Books available for purchase in the Museum Store.
Elizabeth Turk
Elizabeth Turk is a California artist and is represented by Hirschl & Adler Modern. In 2010 she was awarded a MacArthur Fellowship and the Anna & Barnett Newman Foundation award. Born in Pasadena and raised in Orange County, Turk received her MFA from the Maryland Institute College of Art and her BA from Scripps College. She has had a distinguished career internationally and bi-coastally, and her work resides in collections including the National Museum of Women in the Arts, the Weatherspoon Gallery at the University of North Carolina at Greensboro, the Mint Museum, and the Los Angeles County Museum of Art. In 2014-15, Laguna Art Museum presented Elizabeth Turk: Sentient Forms, which included works from the Seashell X-ray Mandala series. In 2018, Turk was the commissioned artist for the museum's Art & Nature.
We look forward
to having you
Recent Happenings
Word & Image in Dialogue
Reception and exhibition of new ekphrastic works created by Laguna Beach writers and artists in a year-long collaborative project.
Auction Tour
Executive director Malcolm Warner and art historian Julia Friedman with a walk-through of the museum's annual art auction.
California Cool Art Auction 2020
With works by important California artists, the annual event includes great art at great prices, delicious cuisine, and creative cocktails.
Receive news about collections, exhibitions, events, and more.


Over 40 years of boat building experience is present in every handcrafted Campion. Our family-based business stretches far beyond our Canadian shores as our boats are seen performing on open waters worldwide. We want your experience to be exceptional. We consider every little detail when it comes to styling, functionality, performance and materials – all of it is carefully balanced and planned to give you the best possible day on the water with your family and friends.


Endgame is an original drama series centering around a brilliant chess master. Using the skills that made him chess champion of the world, Arkady Balagan solves the crimes that mystify others. Traumatized by the murder of his fiancé, Balagan has become a prisoner in his luxury Vancouver hotel, terrified to step outside. To pay his bill, Balagan starts solving mysteries using an unlikely band of hotel employees and chess fanatics to do his legwork. Arrogant, brilliant and charismatic, the Russian-born Balagan is able to envision his unknown opponent's motives and moves. He imagines events, interviews the living and the dead, and runs conflicting scenarios all in his head. And we get to watch right along with him as he solves crimes that baffle the police. In Endgame, we see genius at work.
Balagan is forced to match his chess skills against a computer when his anonymous online opponent reveals that he is playing for lethally high stakes - the lives of a group of innocent hostages.
When the imperious heiress of the Huxley Hotel empire descends for an inspection, she coerces Balagan into helping her find her son, who has mysteriously disappeared.
A mysterious doctor tells Balagan that he is responsible for the murder of a woman found in the hotel pool during a Psychiatric Conference, drawing Balagan into a complex and dangerous game.
When Balagan's oldest friend, the larger than life Russian cosmonaut Oleg Olesky, comes to the Huxley, he brings more than the party. About to pilot the first private space tourism rocket ship, Oleg is there with Chase Galactic as they announce their maiden launch. When the head engineer, Randall, falls from the roof of the hotel, Oleg is the prime suspect. With his only alibi being the fact he was with his boss's wife, which she denies, Oleg pleads for Balagan's help. Balagan eventually figures out the true motive for Randall's murder – and the real murderer.
When the hotel safe is robbed during an extravagant Indian wedding celebration, the distraught couple asks Balagan to help recover their stolen gifts- but is it an inside job or the work of professionals?
Smitten by a beautiful Chinese cryptologist, Sam convinces Balagan to try to solve an intricate puzzle involving a vital secret and an attractive, conniving female journalist.
A well-dressed man wakes up on the sidewalk with no shoes, no wallet, and no memory. The only thing in his pocket is a receipt that leads him to the Huxley Hotel. Remembering nothing but how much he loves his wife, the man hires Balagan to find her and to help him rediscover his identity. While uncovering the truth of the amnesiac's complicated life, Balagan battles with Pippa over the investigation into Rosemary's murder.
Swallowing his pride, Hugo asks Balagan for help. Walt, Hugo's police mentor, is retiring, but one unsolved case still haunts him. Twenty years ago, a teen girl disappeared and Walt is convinced her ex-boyfriend, Stephen, killed her. But because the girl's body was never found, Walt could never charge Stephen. Now with Balagan's help, Hugo hopes to find the one piece of evidence that will put Stephen behind bars before Walt takes matters into his own hands. Pippa comes to Balagan with some startling news in Rosemary's case: the police have finally arrested a suspect.
Balagan's first case is launched when Danni pleads with him to find a missing boy and, in a race against time, he enlists Sam and Alcina to help.
A rock star hires Balagan to find $200,000 stolen from him - a mystery that also involves colourful groupies, a missing polar bear, and the kidnapped grandmother of Danni's estranged husband.
After Balagan investigates the sudden death of a hotel security guard, he is forced to face his worst nightmare.
A daring robbery during a high-stakes poker game forces Hugo to ask Balagan for help, prompting the chess master to create his own complex plot to trap the culprit.
Enlisted by a terrified family to help solve the inexplicable bombing of their car, Balagan is sidetracked by an unexpected match with a 16-year-old world chess champion.


text:
behind the story
Afternoon at semi‑automatic gun club is just like going for round of golf, say organisers
Neil Johnston, Midlands Correspondent
April 15 2019, 5:00pm, The Times
Silverstone Shooting Centre in Northamptonshire, where people take part in "practical shooting"TOM PILSTON FOR THE TIMES
Golf buggies take members to and from a clubhouse against a backdrop of rolling countryside. It is only the sound of gunshots and banners picturing weapons that show this is not your normal sports club.
The Silverstone Shooting Centre in Northamptonshire is one of a number of venues around the country where people can spend their weekends
firing bullets at targets with assault-style rifles, which resemble some of those used in the Christchurch terror attack.
Legally on sale in Britain, shotguns designed to look like AK47 assault rifles similar to those used in the Christchurch attacks have become the gun of choice for participants of "practical shooting", which has a million competitors worldwide and is reputed to be the fastest growing firearms discipline.
Organisers argue…


Dimitri From Paris In The House of Disco is the latest musical milestone from the unequivocal Disco Don; an auditory smorgasbord of House and Disco from the likes of Diana Ross, Hercules & Love Affair, Sister Sledge, Lindstrøm, Chic, Todd Terje, DJ Pierre and many more.
Lindstrøm, Skream and Todd Terje are the stand-out, modern-day champions of the contemporary Disco sound, and all make an appearance here, the latter's electric 'Delorean Dynamite' a neon-fused, hands-in-the-air highlight at the midway point of Dimitri's first mix. Representing true Disco heritage, Tom Moulton reworks Brand New Heavies 'Sunlight', while Dimitri himself gets in on the action, dropping his own remixes of seminal Disco artists Sister Sledge ('Lost In Music'), Diana Ross ('The Boss') and Chic ('LeFreak'), the last two of which are exclusive to this release.
Disc Two celebrates all that is exemplary in 'Neo Vintage House', again matching House masters past and present, occasionally in the same track; the Fingers Acid Jam Vocal Edit of FCL 'It's You' being a standout example. Elsewhere you'll find a group that absolutely embodies the original spirit of House and Disco, the inimitable Hercules & Love Affair who's 'Do You Feel The Same?' closes out the mix.


Edureka, a global e-learning platform for trending technologies, announced that it has entered into a partnership with Electronics & ICT Academy of National Institute of Technology, Warangal (NITW), to introduce a Post Graduate Program in Artificial Intelligence (AI) and Machine Learning (ML). The main aim of the program is to equip professionals for cutting-edge and industry-relevant technologies.
Edureka, being an expert in online learning, will make sure that the program learners receive the best possible experience in learning, it said in a statement.
The association between Edureka and NITW will help the IT professionals in taking charge of their future and becoming experts in the AI and ML space.
"With NIT Warangal and Edureka coming together, it gives us an opportunity to bring you the best of both worlds – Our deep expertise and Edureka's effective learning system and their commitment to excellence. We are confident that participants of this program will emerge as Thought Leaders in AI-ML space and will play a pivotal role in the decades to come," Dr Rao added.
The post graduate program is a 9-month course with more than 450 hours of intensive learning that is designed to make an individual ready to face the challenges of the industry as well as to attain excellence. Learners at the program will be mentored by the professors of NITW. On completion of the course, the individual will receive a PGP certificate and will be considered an alumnus of E&ICT Academy, NITW.
Candidates for the course will be selected on the basis of a thorough online application process and clearing levels of interview rounds.


Northern State Parkway to exit 39, North on Round Swamp Road, Right on Equestrian Court.
Gorgeous large home is being completely renovated on the main floor. We are selling all of the furniture, rugs, chandeliers and even built-ins, everything is going including a custom dream kitchen and everything is mint!!
Costume jewelry, Michele watch and more!!
Fantastic sale, don't miss and bring your tools!!


You need to have a credit card to get register with Score Cards and get reward points according to your purchases. By using your credit card you always get some reward points at your every purchase. These points are mostly based on your purchases if the purchased amount is big the reward points will be more and if the amount is little the reward points will also be less. So no matter you purchased a small thing or big thing you are getting these reward points. You can utilize these reward points on your next visit of the store. You will get some discount or will get any prizes by using your reward points. By using this card you will get one point on spending $1.
This is online process so you need a computer with internet connection to start the process.
If you already had an online account you can carry on with the process.
If you are a new user you can start the process straight away.
Create your online account to carry on with the process.
Provide your personal details so you can get your process completed.
You can withdraw your reward points and also can make purchases of any of their products. You can use these reward points at different hotels and restaurants. You will get some facilities like there is no limit of getting rewards points, it is automatic enrollment and you do not have to pay any fee to use this facility. This facility is totally free and always will be for their best customers.


Founded by North Carolina natives Hans deBot and his wife, Jamye, in 1998, deBotech, Inc., specializes in carbon fiber – a super strong, lightweight material used in everything from sports equipment to electric cars, race cars, planes, sailboat masts, military applications and more to make them lighter, stronger and faster. Since 2002, deBotech has been involved in building bobsleds and skeleton sleds for the U.S. Olympic teams.
"I had a driver come to me and ask if I'd help build a U.S. Olympic bobsled, and I didn't know anything about bobsleds at the time," deBot says.
After researching Olympic rules and regulations, deBot produced an advanced carbon-fiber sled using his knowledge of lightweight racing products, having previously helped develop products for NASCAR and other forms of racing. His sled attracted attention at the 2002 Olympics, and the rest, as they say, is history.
The USA Bobsled and Skeleton Team made history at the 2014 Olympic Winter Games in Sochi, Russia, winning four medals in bobsled events and two in skeleton. They also contributed to winning a gold medal at the 2010 Olympic Winter Games in Vancouver.
"We're really excited about the 2018 Olympics – we hope to win a bunch more medals for our U.S. teams," deBot says.
Building sports equipment is only one of the many industries deBotech serves. The company has built products for General Motors' Corvette and Camaro programs, Chrysler's Viper program, NASCAR and other forms of racing, military, aerospace, and products for everyday people.
People often call deBotech for support in the design of their products.
In 2015, deBot was inducted into the Mechanical and Aerospace Engineering Hall of Fame at North Carolina State University. That same year, deBotech received an industry award from the North Carolina Motorsports Association for positively affecting the motorsports community within the state.
DeBot says he owes a lot of his success to the strong work ethic instilled in him by his mother and his father, who was an immigrant from Holland.
In 2015, deBot was named Mooresville's Businessman of the Year.


Looking for more ways to save on your camping or sports equipment? Then you should become a REI member! This program provides you with exclusive deals and offers you can claim at your local outdoor equipment store.
As a member, you'll gain access to a whole suite of in-store and online benefits. REI not only offers deals and discounts on your favorite sports and camping equipment but also reserves limited-edition gear specifically for members. Throughout the year, REI hosts exclusive events where members gather at the store in their neighborhood to swap discounted sports equipment or to share their experiences on the trail.
To join this amazing community of athletes, backpackers, and globetrotters, visit REI's website and pay your one-time membership fee. Then, stop by your local outdoor equipment store to start saving on your favorite brands.


ALA spokesperson Josh Mennen said that nothing of significance was emerging from the inquiry, and that the government would be wise to heed the growing calls for a Royal Commission into the troubled banking sector.
"The current parliamentary inquiry into banking is inadequate and is proving to be a paper tiger," Mr Mennen said.
"The parliamentary forum format enables the banks to avoid questions by citing 'competitive sensitivities'. There is simply not enough time for issues to be dealt with in more than a superficial glossing over.
"What we are seeing is essentially a PR exercise by the banks, which these bank executives, paid millions of dollars each year, are very good at," Mr Mennen said.
Mr Mennen said the banking practices exposed in recent media reports were a clear sign of deep cultural problems across the sector.
"It's not at all surprising that insurance claims staff have avoided meaningful discipline for mistreating deserving claimants, because claims assessors are encouraged to deny claims to meet their work targets," Mr Mennen said.
Mr Mennen said that the best solution to exposing the cultural issues in the banking sector was to set up a Royal Commission, not the government's proposal to set up a new banking Tribunal.
"Only a Royal Commission can give the necessary level of scrutiny needed to explore and address the systemic problems, by compelling document production and oral evidence under oath," Mr Mennen said.
"To do that, we need a Royal Commission conducted with openness and transparency," Mr Mennen said.
lame product development including the exorbitant credit card rates and outdated insurance definitions.
Mr Mennen said that other actions could also be implemented quickly to help end the cultural problems endemic in the banking sector. These included improving the protections offered to whistleblowers, with consideration given to the US-style incentive model, and a 'scheme of last resort' to compensate financial services victims where their financial services provider goes bust and is unable to pay compensation.


text:
The 2019 Liga Profesional de Primera División season, also known as the Campeonato Uruguayo 2019, was the 116th season of Uruguay's top-flight football league, and the 89th in which it is professional. The season was named as "100 Años de Racing Club de Montevideo" and was originally scheduled to begin on 9 February but its start was pushed back for one week to 16 February. The season ended on 15 December with Nacional winning their forty-seventh title by beating Peñarol in the semifinal. Peñarol were the defending champions, having won back-to-back titles in 2017 and 2018.

Teams

El Tanque Sisley, who did not compete in the 2018 season, as well as the two bottom-placed teams in the relegation table of the 2018 season, Torque and Atenas, were relegated to the Segunda División for the 2019 season. They will be replaced by Cerro Largo, Juventud, and Plaza Colonia, who were promoted from the Segunda División.

Managerial changes

Torneo Apertura
The Torneo Apertura, named "Sr. Juan Lazaroff", was the first tournament of the 2019 season. It began on 16 February and ended on 5 June.

Standings

Results

Top goalscorers

Source: Soccerway

Torneo Intermedio
The Torneo Intermedio was the second tournament of the 2019 season, played between the Apertura and Clausura tournaments. It consisted of two groups whose composition depended on the final standings of the Torneo Apertura: teams in odd-numbered positions played in Serie A, and teams in even-numbered positions played in Serie B. It started on 13 July and concluded on 8 September, with the winners being granted a berth into the 2020 Copa Sudamericana and the 2020 Supercopa Uruguaya.

Serie A

Serie B

Torneo Intermedio Final

Top goalscorers

Source: Soccerway

Torneo Clausura
The Torneo Clausura, named "Sr. Franz Oppenheimer", was the third and last tournament of the 2019 season. It began on 14 September and ended on 11 December.

Standings

Results

Torneo Clausura decider
Since Nacional and Peñarol ended up tied in points for first place, an additional match was played by both teams to decide the Torneo Clausura winners. Nacional won this match and qualified for the semifinal.

Top goalscorers

Source: Soccerway

Aggregate table
The aggregate table includes the results of the three stages played throughout the season: Torneo Apertura, Torneo Intermedio, and Torneo Clausura. The top team at the end of the season will qualify for the finals of the championship playoff.

Championship play-off

Semi-final

Final
Since Nacional, who had the best record in the aggregate table, won the semi-final, they became champions automatically and the final was not played. Peñarol became runners-up as the second-placed team in the aggregate table. Both teams qualified for the 2020 Copa Libertadores group stage.

Relegation
Relegation is determined at the end of the season by computing an average of the number of points earned per game over the two most recent seasons: 2018 and 2019. The three teams with the lowest average were relegated to the Segunda División for the following season.

References

External links
Asociación Uruguaya de Fútbol - Campeonato Uruguayo

2019
2019 in South American football leagues
2019 in Uruguayan football


Your dogs and cats teeth should be checked once a year by your vet.
Brushing your pet's teeth on daily basis can keep their teeth healthy between dental visits. It can eliminate the need for dental cleaning. If you see any of these signs you might have to see your vet sooner: Broken or loose teeth, bleeding gums, lack of appetite, bad breath, abnormal drooling, brown or discolored teeth, extra teeth or retained baby teeth.
Periodontal disease is caused by bacteria in dental plaque. Bacteria causes inflammation of the gums.
Gingivitis: the gums become red swollen and can bleed easily. A mild gingivitis can be reversed with daily brushing.
Only use a pet teeth brush. At first, you might want to use the rubber finger toothbrush that fits over your finger until your pet gets used to you brushing its teeth. The toothbrush is better for plaque removal.
Only use pet toothpaste, usually, the pets like the one that comes in flavors. Try different flavors until you find the one that your pet likes. Let the pet smell it first and taste it.
Put the leash on your dog this will help to control your dog and keep it from escaping.
You should be more concerned with the outside like the large fangs, the front of the mouth, the teeth and gum line. The tongue does a good job with inside area of the mouth.
Keep the tooth brushing sessions short with lots of praise and affection.
Some cats do not like to drink from the water bowl and prefer to dip their paws in the water and lick their paws.
Other cats prefer running water from the kitchen sink, bathtub, dripping faucet in the bathroom.
The cat will come running when it hears running water.
Cats don't like pressure on their whiskers when they eat or drink, it's called whisker stress.
Be sure you use filtered water to remove contaminants in the water, like arsenic, lead, chlorine, and bacteria.
temperature is cooler in the toilet.
Caution! Do not let the cat drink from the toilet bowl. The chemicals and bacteria can make a cat sick.
Kittens will begin to drink water around 3-4 weeks of age. Use a shallow water dish.


This place is a gem. Having spent the last five days walking, running, yoga and surfing, my entire body was in need of rejuvenation. I highly recommend Angie because she is an excellent masseuse and seems to genuinely care about her clients. I will return again.
Atmosphere and Decor: Almost a trip to serenity within a Thai Buddhist temple with angelic female monks. Calm-Tranquil nothing unclean or semi-shady here!
, her strength and intuition could only be from years of experience , exceptional training and a true passion for her work.
Prices: Higher than San Diego Chinese massages but the norm for OC. Bottom line an exceptional value!
And these guys are definitely on that list!
I was experiencing a lot of pain in my back & neck to the point I couldn't handle it any longer. I've had 100's of massages, but never a Thai massage.
Angie was amazing! I'm hooked. Angie was polite, friendly, easy to talk with & is a great masseuse! I walk out feeling 100% better. My pain nearly disappeared. I was so grateful!
Through the end of the month massages are 15% off! I paid $55 plus tip for an hour massage.
I'll definitely return!! Thanks Angie.
Beauty was an incredible masseuse. She made sure to check in with me about whether the pressure was too strong and was very thorough. I feel extremely loose and flexible. I will be back!


A nauseating stench fills the air almost as soon as the boat turns south, leaving behind the ancient harbour of Sidon.
"It's horrible isn't it? You smell it before you can see it," Mohammad, a fisherman, said as he steers the vessel.
It takes another 10 minutes for the source of the stench to appear- a giant mountain of rubbish, as tall as a four floor building. It seems to rise out of the sea.
The Sidon rubbish dump has been growing for almost 30 years.
Environmental campaigners in Lebanon say the government must solve what they say is a catastrophe for the local ecosystem.
It is also a disaster for Mohammad and his fellow fishermen.
Mohammad blames the rubbish mountain for his thinning catches and says the waste gets caught in his fishing nets.
"A set of nets costs about US$500," he said. "We keep losing our nets, and we don't have money to replace them. The government is doing nothing about this."
The dump, set right next to the ruins of an old Jewish cemetery, towers over the city of Sidon.
It was originally created to dispose of the remains of buildings destroyed in Israeli airstrikes during the 1982 invasion.
But ever since it has served as the main disposal site for the city.
Every day lorries carry rubbish to the top of the hill, where they are greeted by a group of a dozen or so men and a few packs of dogs which live at the dump.
The scavengers, most of whom are Palestinian refugees, sort the rubbish, picking out anything they can sell on.
"Metal, plastic, glass is what we look for," said Mohammad Hamdan, a 30-year-old scavenger.
He has worked at the dump since he was 10 years old and says he makes about US$10 dollars a day.
"Some of us here are well-educated, some even have university degrees, but there are no jobs for us in Lebanon," Mr Hamdan said.
He says he hates his job, but believes that the only alternative to it is begging.
"You can never get used to the smell. And in the summer, when its hot, the stench is just unbearable," said Mr Hamdan.
Environmentalists say that along with the smell, the dump is a health hazard.
Industrial, some chemical and even medical waste is dumped at the site along with household rubbish.
Men who work at the site say hospitals from the area regularly bring their rubbish to the dump.
"Its full of syringes, blood, flesh, even kidneys," Mr Hamdan cringes as he describes the hospital waste.
Much of it ends up in the Mediterranean sea. The dump is sliding into the water.
Even though there there have been no comprehensive studies on its effect to humans and marine life, environmentalists insists that it is damaging.
"Toxins that are leaking into the sea pose a threat to the marine life, and to the eco-system along the Mediterranean coast," said Garabed Kazanjian, oceans campaigner for Greenpeace.
Mr Kazanjian says it is possible to solve the problem.
A plan for moving the site has been worked out and there are donor funds available.
But there is a lack of political will. For years, Lebanon's divisive sectarian politics have stood in the way of removing the dump.
Various government agencies blame each other for the problem, each refusing to take charge.
"The plan is in place, money is there, the only thing that's missing is a political decision. But until these politicians start thinking about the benefit of people and the ecosystem, this issue will not be solved," says Mr Kazanjian.


text:
Teufelsbach may refer to the following rivers in Germany:

 Teufelsbach (Rhynerscher Bach) of North Rhine-Westphalia, a tributary of the Rhynerscher Bach
 Teufelsbach (Müggenbach) of North Rhine-Westphalia, a tributary of the Müggenbach which is itself a tributary of the Morsbach
 Teufelsbach (Alaunbach) of North Rhine-Westphalia in the Beuel district of Bonn
 Teufelsbach (Goldbach) of Saxony-Anhalt in the county of Harz

See also
 Teufelsgrundbach, a tributary of the River Selke in the Lower Harz in Saxony-Anhalt